Heavy metals are a heterogeneous group of highly reactive substances, which may act as essential cofactors for physiologic processes and/or as toxic elements. Chromium, in particular, has been associated with obesity, diabetes, and weight loss. Other heavy metals have been associated with some of the consequences of obesity, including hypertension, hyperlipidemia, and cardiovascular disease. The Look AHEAD Study, a large randomized controlled trial of intensive lifestyle intervention for weight loss in obese patients with Type 2 diabetes mellitus, provides an excellent opportunity to address the impact of chromium on weight loss and diabetes control, as well as to assess the impact of other heavy metals on the physiologic consequences of weight loss. We propose an ancillary prospective observational study within the Look AHEAD trial to collect toenail clippings from all participants (n = 5,000) at baseline and at the 1-year visit, and to analyze a random subset of the toenails (1,150 baseline toenails and 480 1-year visit toenails) for their heavy metal content using instrumental neutron activation analysis. Toenails provide a time-integrated measure of heavy metal exposure, while instrumental neutron activation analysis provides the concentrations of about 50 heavy metals in the toenail samples, including chromium. This information will allow us to evaluate the relationship of baseline toenail chromium concentrations to weight loss, as well as the interaction between heavy metals and the beneficial effects of weight loss. The proposed study may provide, valuable insight into the determinants of the efficacy of weight loss interventions. In fact, the Look AHEAD trial, because of its size, may be one of the few studies in which these relationships can be measured reliably. In addition, the ancillary study will permit the setup of a specimen bank of toenails to be used in future case-cohort or nested case-control studies of the association of heavy metals with Look AHEAD endpoints, especially myocardial infarction and cardiovascular death.